How A Painkiller Designed To Deter Abuse Helped Spark An HIV Outbreak

Volunteers search for used needles near Rural Street in Austin, Ind. Scott County, in southeastern Indiana, experienced the worst outbreak of HIV in the state's history after people began injecting the prescription painkiller Opana.

A reformulated OxyContin pill (left) releases its active ingredient over time, but an added polymer makes it difficult to crush, melt or prepare for injection. When heated, the polymer forms a viscous gel that binds the active ingredient.

But the drug's manufacturer, Endo Pharmaceuticals, reformulated Opana in 2012. The new pills featured a coating that was intended to make them more difficult to abuse by crushing them into powder or dissolving them.

Polly discovered he could no longer snort the medicine in the pill, to which he had become addicted. But he and other Opana users soon found a way to remove the drug's hard coating and receive Opana's powerful dose all at once: injection.

Polly says he used to inject Opana as many as five times a day. He often shared needles with other people.

He says he never anticipated what would happen next. In early 2015, Polly tested positive for HIV. "It was devastating news," he says.

Kevin Polly is among the 190 people in Indiana's Scott County who have tested positive for HIV since early 2015, in the largest HIV outbreak in Indiana history.

The Change To Opana That Was Intended To Prevent Abuse

For its part, Endo has said that its decision to reformulate Opana was a well-intended attempt to prevent abuse. As the company told the Food and Drug Administration in 2012, Endo reformulated the drug "to provide a crush-resistant product, equally as effective as Opana ER, which would discourage abuse, misuse and diversion." Endo declined repeated requests from NPR for an interview.

According to study data, as well as interviews with Indiana residents addicted to Opana, the reformulation effectively deterred many people from snorting the drug. But the change also led a significant number of people to abuse the drug by injection. When needles are shared, the injection route can transmit HIV, hepatitis C or other infections.

And interviews with experts, court filings, documents from the FDA, as well as Endo's own statements, suggest the company's decision to reformulate Opana was also motivated in large part by financial interests.

Public health experts say "abuse deterrent" drugs may serve a role in reducing what the Centers for Disease Control and Prevention calls a national epidemic of prescription opioid abuse. The FDA and members of Congress have also supported their development. But the experience with Opana's reformulation may serve as a cautionary tale for the potential effects of "abuse deterrent" drugs.

Experiences In Austin, Ind.

While NPR's Kelly McEvers and I were reporting in Austin, Ind., people who abused Opana and were familiar with changes to the drug's formula told us similar stories.

"The pharmaceutical company, they changed it so you can't crush them and snort them," said Devin, a 26-year old. "Whenever they done that, that's when everybody started shooting them."

Jeff, a veteran of the Army National Guard, said he became addicted to Opana after being prescribed opioid painkillers for a back injury he sustained in Iraq.

At some point, Jeff said, he began crushing and snorting pills. Then, he said, the company "reformulated them, and the only way you could do them is to inject them."

Joy, a former registered nurse who got addicted to opioids after a back injury, said that she initially stopped using Opana after the reformulation. But that didn't last long. "Some genius figured out, 'Hey we can cook this down and turn [it] into a liquid and shoot it up,' " Joy said. "And then it took off like wildfire after that."

(NPR is withholding Devin's, Jeff's and Joy's last names to protect their privacy.)

Because of the coating added to Opana, the process of preparing it for injection does take a little work. But in the end, it's not that difficult.

My colleague Kelly watched people prepare Opana for injection, using just the bottom of a soda can, a small lighter, a cigarette filter and tap water.

Behind The Reformulation, Public Health And Business Considerations

So why did Endo Pharmaceuticals reformulate the drug in the first place?

The answer involves both public health concerns and business considerations.

Endo Pharmaceuticals released Opana in 2006. Taken orally, Opana is about twice as powerful as OxyContin, and the company says it is "indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment."

Soon afterward, though, communities around the country began reporting abuse of Opana and even overdose deaths.

Endo said those concerns over public health and abuse were key motivations to reformulate the drug. Opana also was a major moneymaker for the company.

So Endo developed a strategy that would block its competitors and maintain Opana's share of the market.

The company reformulated the drug, this time with features designed to prevent abuse, a move that could potentially protect Endo at a time it faced the loss of patent protection.

The FDA approved Endo's reformulated Opana, and in 2012 the company began replacing the old versions of Opana on pharmacy shelves.

In August of that year, Endo took another step. The company filed a petition with the FDA, arguing that it had removed the old, crushable version of Opana from the market "for reasons of safety or effectiveness." It also asked the agency to "refuse to approve" and "suspend and withdraw the approval" of generic, noncrush-resistant versions of Opana.

If the FDA agreed with Endo, the agency would effectively eliminate the company's generic competition.

"We see this again and again in the pharmaceutical industry," says Dr. Anna Lembke, an assistant professor of psychiatry at Stanford University Medical Center. "They come up with some new fancy formulation of basically the same old drug ... and then that way they have a new drug that they can charge a lot of money for."

For example, in 2010, Purdue Pharma reformulated its popular opioid painkiller OxyContin to make the drug crush-resistant. The FDA later determined that the reformulated version of OxyContin was significantly safer and that "the benefits of original OxyContin no longer outweigh its risks."

The agency then blocked generic, noncrush-resistant versions of OxyContin. Dr. Andrew Kolodny, executive director of Physicians for Responsible Opioid Prescribing and a prominent critic of the drug industry, says this type of decision "is worth billions to a pharmaceutical company."

In 2012, while Endo's petition was pending FDA's decision, the company filed a lawsuit in U.S. District Court for the District of Columbia to compel the agency to speed up the review.

Endo's lawyers predicted a "spike of misuse and abuse" if generic — and noncrush-resistant — versions of Opana hit the market.

But the company also acknowledged its business interests.

In a signed declaration, Julie H. McHugh, then the chief operating officer at Endo, said that if a generic version of Opana entered the market, "annualized net sales will decrease by an amount up to $135 million."

The loss in sales, McHugh stated, "could result in the termination of up to 150 employees and contractors employed by Endo."

The FDA said that profits — not public health – were behind Endo's impatience.

"Endo's true interest in expedited FDA consideration stems from business concerns rather than protection of the public health," lawyers for the agency stated in a legal filing.

Opana was still safe and effective when appropriately prescribed, the FDA said.

But the agency said, "study data show that the reformulated version's extended-release features can be compromised when subjected to ... cutting, grinding, or chewing." The FDA also determined that "reformulated Opana ER can be readily prepared for injection."

Significantly, the agency warned that preliminary data about how the drug was being abused suggested "the troubling possibility that a higher percentage of reformulated Opana ER abuse is via injection than was the case with the original formulation."

Unintended Consequences

By the time the FDA concluded that reformulated Opana didn't effectively deter abuse, warning signs had already appeared.

In a conference call with investors on Feb. 28, 2013, Endo officials were asked about the reports of injection abuse. "We've designed the Opana crush-­resistant formulation to be crush­-resistant, to avoid primarily the nasal root of abuse," said Ivan P. Gergel, who served as Endo's chief scientific officer at the time. Gergel didn't say whether intravenous abuse was considered in developing the drug's reformulation.

"Clearly, we are looking into this data," Gergel went on to say, "but it's in a very, very distinct area of the country."

Subsequent analyses of drug abuse dataappear to contradict Gergel's claim and support the FDA's concerns about injection abuse.

One study from 2014, co-authored by an Endo medical director, drew from data collected at drug treatment centers around the U.S. Overall abuse of Opana had dropped following reformulation, the authors found. But injection had become the preferred way of abusing the drug.

According to the study, 64 percent of people abusing reformulated Opana were injecting the drug, between October 2012 and March 2014. By comparison, 36 percent of people abusing the noncrush-resistant versions of Opana did so by injection.

"With the reformulation, snorting appears to be much, much lower, whereas injection appears to be the more preferred route," Theresa Cassidy, the study's lead author, told NPR in a phone interview. Still, Cassidy, a vice president of analytics at a company called Inflexxion, warns that it's not possible to draw a causal link between the reformulation and injection abuse based simply on these data.

(Inflexxion is paid by pharmaceutical companies, including Endo, to conduct research into drug abuse patterns but says it maintains independence.)

A separate study also looked at abuse data before and after Opana's reformulation. Though the sample size was small, the study found "a trend toward increases in IV [intravenous] use after the reformulation."

Endo's Response

NPR asked Endo for an interview related to abuse issues of Opana and the company's decision to reformulate the drug.

"Patient safety is a top priority for Endo and we are committed to providing patients with approved products that are safe and effective when used as prescribed," the company said in a statement in response. "We are dedicated to providing quality medications for the treatment of patients diagnosed with chronic pain as well as to addressing opioid misuse and abuse."

While declining an interview, Endo directed NPR to contact the Center for Lawful Access and Abuse Deterrence, a nonprofit organization that advocates for the development of prescription drugs with abuse-deterrent technology. "I think that you've got a problem where the product isn't able to deter all forms of abuse," says Mike Barnes, the executive director of CLAAD. "But to the extent that it's possible to avoid inhalation, for example, the snorting, that has a benefit."

The FDA has called the development of abuse-deterrent drugs a "high public health priority." In response to this story, agency spokeswoman Sarah Peddicord tells NPR in an email, "The FDA is very concerned about potential unintended consequences of abuse-deterrent opioids (and purportedly abuse-deterrent opioids) and it is something we are actively looking at."

Peddicord reiterated the FDA's decision not to approve abuse-deterrent labeling for Opana, and says it is continuing to monitor the five drugs the agency has approved as abuse-deterrent.

"FDA is requiring all sponsors of opioids with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in the real world," says Peddicord. "Abuse-deterrent does not mean abuse-proof."

The idea of deterrence could give doctors and patients a false sense of security, since the underlying opioid is just as addictive, some experts warn.

"The two most important things that we can do to address the opioid epidemic are to prescribe fewer opioids, and to get patients with opioid addiction into treatment," says Dr. Caleb Alexander, co-director of the Johns Hopkins Center for Drug Safety and Effectiveness. "And there's no evidence to suggest that abuse-deterrent formulations are going to fundamentally change the shape of the opioid epidemic."

Endo Continues To Seek Abuse-Deterrent Status For Opana

Despite the well-publicized accounts of abuse in Indiana and Tennessee, Endo continues to push for FDA labeling that would call reformulated Opana ER "abuse-deterrent," because of its apparent effect on abuse by snorting.

In a call with investors on Feb. 29, 2016, President and CEO Rajiv De Silva said that, for the most part, "If we are successful in getting that relabeling, it will certainly serve to help remove all the generics from the market."

Endo's push for relabeling may face additional scrutiny because of ongoing legal inquiries. In February, the New York attorney general said Endo engaged in "deceptive and unlawful conduct" in its marketing of Opana and imposed a $200,000 penalty on the company.

The company's statement to NPR said, "The settlement does not include any agreement or confirmation by Endo that its marketing practices were inappropriate."

On Thursday, the Federal Trade Commission also announced a lawsuit filed in U.S. District Court for the Eastern District of Pennsylvania against Endo alleging that the company violated antitrust laws and illegally blocked access to generic versions of Opana. Endo says in a statement, "We believe the FTC's case is without merit and Endo intends to vigorously defend itself in the litigation."

Back in Austin, Ind., local, state and federal law enforcement have struggled to eliminate Opana from the town's illegal-drug market.

But drug users there still describe Opana as the most desirable drug around.

A single Opana pill, they say, now costs about $200, up from around $140 when we started reporting this story.

Side Effects Public Media health reporter Jake Harper and NPR's Kelly McEvers contributed to this story.

Copyright 2018 NPR. To see more, visit http://www.npr.org/.

ARI SHAPIRO, HOST:

The small town of Austin, Ind., is still coping with an HIV outbreak that began more than a year ago. A-hundred-ninety people have tested positive for HIV in a town of about 4,500. As we heard yesterday, the outbreak is tied to IV drug use and people sharing needles.

AUDIE CORNISH, HOST:

The drug of choice in Austin is a prescription painkiller called Opana, specifically a version of Opana that was supposed to be abuse-deterrent. Our colleague, Tom Dreisbach, has been looking into this drug and the company that makes it, Endo Pharmaceuticals. Our co-host, Kelly McEvers, spoke to him about his reporting.

KELLY MCEVERS, HOST:

Tom, what did you find out about this drug, Opana?

TOM DREISBACH, BYLINE: So Opana came out in 2006. It's about twice as powerful as OxyContin, and it's indicated for moderate-to-severe chronic pain. And like a lot of opioids these days, it's been abused. Many people were crushing and snorting the pills. And what I found is that, in 2012, Endo Pharmaceuticals reformulated this drug. They added a coating that they said would make it crush-resistant. Now, that change seems to have had an unintended consequence. We talked to people in Austin who had been snorting this drug. They told us, after the reformulation, that's when they starting using needles to inject it. And I found evidence that this has been happening in other parts of the country, too..

MCEVERS: What has the company said about this?

DREISBACH: Well, Endo declined to talk on tape. In a statement, they told us, quote, "were dedicated to providing quality medications to treat the millions of patients diagnosed with chronic pain and to addressing opioid abuse." What I found is that they had both public health motivations, and interviews with experts, court filings and documents suggest they also had real business motivations for reformulating this drug.

MCEVERS: We're going to talk about that more in a minute, but first let's talk about some of the stories we heard while we reporting on this in Indiana.

DREISBACH: Right, well, there was this one woman named Joy. We're only using her first name to protect her privacy. She's a former registered nurse. She had a back injury, got prescribed painkillers, got addicted to those painkillers. And at some point, she started snorting Opana. Now, when the company reformulated the drug in 2012, she could not snort the drug anymore, but then she told us...

JOY: Some genius figured out, hey, we can cook this down and turn it into a liquid and shoot it up. And then it took off like wildfire after that. Everywhere you look in town was just sharing needles, and you saw where that led, you know - the HIV outbreak.

DREISBACH: Now, Joy says she's lucky. She didn't share needles, and she has tested negative for HIV. But we heard the same story again and again from people in Austin, Ind.

MCEVERS: We did. And while we were there, I watched, actually, how people cook Opana in the bottom of a soda can. All it took was a cigarette lighter and some tap water, and the coating on this pill just floated away. So the question is, why did the drug company change the drug?

DREISBACH: Well, Endo has maintained that the decision was about public health. They told the Food and Drug Administration that they wanted to make a drug that was just as effective and harder to abuse, but I found documents that suggest a strong financial motivation for this change. At the time, Endo was facing the threat of generic competition. And so when they reformulated the drug in 2012, they filed a petition with the FDA. They asked that their new drug get official labeling calling the drug abuse-deterrent. And they also asked the FDA to block all of their generic competitors. In a signed declaration, an Endo executive said that if generic competition came on the market, that would reduce sales of Opana by up to $135 million every year.

MCEVERS: Did Endo get what it wanted?

DREISBACH: No. The FDA rejected Endo's petition. They said they do not consider the drug abuse-deterrent. At the time, they wrote, quote, "reformulated Opana can be readily prepared for injection." They also said preliminary data suggests, quote, "the troubling possibility that a higher percentage of reformulated Opana abuse is via injection than was the case with the original formulation." That was the FDA. And I found two separate studies that seem to confirm the FDA's fears. The studies found, overall, Opana abuse had dropped after the reformulation, especially among people who snorted the drug. But according to one study co-authored by a medical director from Endo, most of the abuse of Opana is now by injection.

MCEVERS: So what does this mean for the bigger picture - I mean, the overall opioid crisis in this country?

DREISBACH: Depends on your perspective. I mean, people who support the development of abuse-deterrent drugs say they're not perfect, but stopping some forms of abuse, like snorting, is worthwhile. On the other hand, public-health experts worry that these drugs give a false sense of security. They say the abuse-deterrent versions do not stop people from abusing them orally. And there's this real worry that preventing one type of abuse for one drug without also increasing access for drug treatment just shifts people to using other painkillers or illegal drugs, like heroin. You know, the FDA has encouraged these reformulations because they think they can at least help with the country's opioid problems. And they've actually approved abuse-deterrent labeling for five opioid painkillers so far. An agency spokesperson told me they are monitoring all of those drugs very closely and that they are, quote, very concerned about potential unintended consequences.